Missing molecules hold promise of therapy for pancreatic cancer

By determining what goes missing in human cells when the gene that is most commonly mutated in pancreatic cancer gets turned on, Johns Hopkins scientists have discovered a potential strategy for therapy.

The production of a particular cluster of genetic snippets known as microRNAs is dramatically reduced in human pancreatic tumor cells compared to healthy tissue, the researchers report in a study published Dec. 15 in Genes and Development. When the team restored this tiny regulator, called miR-143/145, back to normal levels in human pancreatic cancer cells, those cells lost their ability to form tumors.

"Our finding that these specific microRNAs are downstream of the most important oncogene in pancreatic cancer sets the stage for developing methods to deliver them to tumors," says Josh Mendell, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, and an early career scientist of the Howard Hughes Medical Institute. "When we restore microRNAs to cancer cells in which their levels are repressed, the cells no longer are tumorigenic. We have every reason to believe that the efficient delivery of miR-143/145, if achievable, would be therapeutically beneficial."

The team focused its investigation on KRAS, a member of the important RAS family of oncogenes that is mutated in almost all cases of the most common form of pancreatic cancer.

The researchers conducted their studies in a multitude of model systems — human cells growing in culture as well as those harvested directly from tumors, and also in mice and zebrafish. First, using cell lines derived from pancreatic tumors and growing in culture, they added gene products such as mutant KRAS and an inhibitor of mutant KRAS, and then measured the microRNA responses. Next, they conducted the same experiments using cells from patients' pancreatic tumors. Finally, they looked at pancreatic tissue from mice and zebrafish to see what happened when KRAS was activated.

Every time, the team noted the same robust findings. When KRAS was activated, the microRNA cluster miR-143/145 was powerfully repressed, to a fraction of the levels in normal, non-cancerous cells. Restoring the expression of miR-143/145 back to the level of normal cells was sufficient to confer "a very striking change in behavior of those cells," Mendell says. When human pancreatic cancer cells with low microRNA levels were injected into mice, they formed tumors within 30 days. However, when the team restored the levels of microRNAs to the levels of normal cells and injected them into mice, tumors failed to form.

"Our findings showed that repression of the miR-143/145 microRNA cluster is a very important component of the tumor-promoting cellular program that is activated when KRAS is mutated in cancer cells," says Oliver Kent, a postdoctoral fellow in the Mendell laboratory and first author on the paper.